Constrained cyano compounds

• US 20060009518A1
• Filed: 07/12/2005
• Published: 01/12/2006
• Est. Priority Date: 07/12/2004
• Status: Active Grant

• Current Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Original Assignee: Forest Laboratories Holdings Limited (Abbvie Incorporated)
• Inventors: Winn, David T., Campbell, David Alan, Betancort, Juan Manuel
• Granted Patent: US 7,786,163 B2
• Time in Patent Office: Days
• US Class Current: 514/522
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/06 : of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
• CPC Class Codes: A61P 5/28 : Antiandrogens
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems

Abstract

Certain constrained cyano compounds are useful as inhibitors of post-proline/alanine cleaving amino-dipeptidases. Accordingly, these compounds can be employed, alone or with another therapeutic agent, to treat diabetes (especially, Type II diabetes), hyperglycemia, Syndrome X, diabetic complications, hyperinsulinemia, obesity, atherosclerosis and related diseases, as well as various immunomodulatory diseases and chronic inflammatory bowel disease.

Claims

1. The compound of Formula I:

2. The compound of claim 1 wherein X is CH₂, S, or O.

3. The compound of claim 1 wherein X is S or O .

4. The compound of claim 1 wherein R¹ and R⁴ are independently:

a) H;

b) (C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12)cycloalkyl, (C_3-12)(cycloalkyl)alkyl, (C_3-12)cycloalkenyl, or (C_3-12)(cycloalkenyl)alkyl;

wherein each group is optionally mono- or independently plurisubstituted with R⁷, and wherein the alkyl, alkenyl, and alkynyl groups optionally and independently comprise 1, 2, or 3 groups selected from O, NH, S, SO, SO₂, or a 3, 4, 5, or 6 member divalent carbocyclyl or heterocyclyl group;

wherein

R⁷ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_3-10)cycloalkyl;

—

SR⁸;

—

SOR⁸;

—

SO₂R⁸;

—

COR⁸;

—

CO₂R⁸;

—

CONHR⁸;

—

CON(R⁸)₂;

—

OC(O)NHR⁸;

—

OC(O)N(R⁸)₂, —

OR⁸;

carboxy;

cyano;

nitro;

oxo;

hydroxyl;

hydroxy(C_1-6)alkyl;

hydroxymethyl;

N-hydroxyimino;

trifluoromethyl;

trifluoromethoxy;

sulfamoyl;

sulfonamido;

carbamoyl;

azido;

amidino;

guanidino;

amino, wherein the amino group is optionally mono- or independently plurisubstituted with R⁸, —

SOR⁸, —

SO₂R⁸, —

COR⁸, —

CO₂R⁴, —

CONHR⁸, —

CON(R⁸)₂, —

OR⁸, or —

SR⁸;

aryl;

heterocyclyl;

or heteroaryl;

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

each R⁸ is independently (C_1-10)alkyl;

(C_2-10)alkenyl;

(C_2-10)alkynyl;

(C_3-10)cycloalkyl;

(C_5-10)cycloalkenyl;

benzyl;

phenethyl;

aryl;

heterocyclyl, or heteroaryl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups are optionally mono- or independently disubstituted with R¹⁰; and

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R¹¹;

R⁹ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_3-10)cycloalkyl;

—

SR⁸;

—

SOR⁸;

—

SO₂R⁸;

—

COR⁸;

—

CO₂R⁸;

—

CONHR⁸;

—

CON(R⁸)₂;

—

OC(O)NHR⁸;

—

OC(O)N(R⁸)₂, —

OR⁸;

carboxy;

cyano;

nitro;

oxo;

hydroxyl;

hydroxy(C_1-10)alkyl;

hydroxymethyl;

N-hydroxyimino;

trifluoromethyl;

trifluoromethoxy;

trifluoromethylthio, sulfamoyl;

sulfonamido;

carbamoyl;

amidino;

guanidino;

phenyl, phenoxy, benzyl;

benzyloxy;

azido;

amino, wherein the amino group is optionally mono- or independently plurisubstituted with R⁸, —

SOR⁸, —

SO₂R⁸, —

COR⁸, —

CO₂R⁸, —

CONHR⁸, —

CON(R⁸)₂, —

OR⁸, or —

SR⁸;

(C_1-10)alkylamino;

or (C_1-10)dialkylamino;

R¹⁰ is aryl, heterocyclyl, or heteroaryl, wherein each group is optionally mono- or independently plurisubstituted with R¹¹;

R¹¹ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_1-10)alkylamino;

(C_1-10) dialkylamino;

phenyl, phenoxy, benzyl;

benzyloxy;

hydroxyl(C_1-6)alkyl;

hydroxymethyl;

nitro;

trifluoromethyl;

trifluoromethoxy;

trifluoromethylthio;

N-hydroxyimino;

cyano;

carboxy;

acetamido;

hydroxy;

sulfonamido;

or amino;

c) phenyl, phenyl fused to a (C_3-10)cycloalkyl;

monocyclic heteroaryl, or monocyclic heteroaryl fused to a (C_3-10)cycloalkyl;

wherein the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

d) indanyl;

1,2,3,4-tetrahydronaphthyl;

—

(CH₂)_j-adamantyl in which j is 0, 1, 2, or 3;

(4-pentylbicyclo[2.2.2]oct-1-yl)amine;

or a [2.2.1] or [3.1.1] bicyclic carbocyclyl group, wherein the indanyl, 1,2,3,4-tetrahydronaphthyl, —

(CH₂)_j-adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclyl groups are optionally mono- or independently plurisubstituted with hydroxy, (C_1-8)alkyl, (C_1-8)alkoxy, (C_1-8)alkanoyloxy, or R¹²R¹³ N—

CO—

O—

, wherein R¹² and R¹³ are independently (C_1-8)alkyl, or phenyl, wherein the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C_1-8)alkyl, (C_1-8)alkoxy, halogen, or trifluoromethyl, or R¹² and R¹³ together are (C_3-6)alkylene;

e) R¹⁴(CH₂)_p—

wherein R¹⁴ is pyrrolyl, pyrrolidinyl, 2-oxopyrrolidinyl, imidazolyl, pyrazolyl, thiophenyl, thiazolyl, furanyl, tetrahydrofuranyl, oxazolyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, purinyl, pyrimidinyl, quinolinyl, (C_1-6)alkoxy, phenyl, phenoxy, (C_1-8)cycloalkyl, naphthyl, cyclohexenyl, or adamantyl;

each of which groups is optionally mono- or independently di- or trisubstituted with R¹⁵;

or R¹⁴ is a [3.3.3] bicyclic carbocyclyl group, optionally mono-or independently plurisubstituted with (C_1-8)alkyl; and

p is 0, 1, 2, or 3; and

wherein

R¹⁵ is halogen;

cyano;

nitro;

(C_1-6)alkyl;

(C_1-6)alkoxy;

cycloalkyl;

carboxy;

C(O)NHR⁸;

hydroxy;

hydroxy(C_1-6)alkyl;

hydroxymethyl;

trifluoromethyl;

trifluoromethoxy;

sulfamoyl;

carbamoyl;

sulfonamido;

aryl;

heterocyclyl;

or heteroaryl;

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

or

f) (R¹⁶)₂CH(CH₂)_q—

, wherein R¹⁶ is phenyl;

in which the phenyl groups are independently optionally mono- or independently disubstituted with R¹⁵; and

q is 0, 1, 2, or 3.

5. The compound of claim 4 wherein R¹ and R⁴ are independently

a) H;

b) (C_1-12)alkyl, (C_2-2)alkenyl, (C_2-2)alkynyl, (C_3-2)cycloalkyl, or (C_3-12)cycloalkenyl;

wherein each group is optionally mono- or independently plurisubstituted with R⁷;

c) phenyl, phenyl fused to a (C_3-10)cycloalkyl, monocyclic heteroaryl, or monocyclic heteroaryl fused to a (C_3-10)cycloalkyl;

wherein the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

d) R¹⁴(CH₂)_p—

;

or

e) (R¹⁶)₂CH(CH₂)_q—

.

6. The compound of claim 1 wherein R¹ is H or a R¹ is H or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopentyl, cyclopentyl-(CH₂)—

, cyclohexyl, cyclohexyl-(CH₂)—

, phenyl, benzyl, phenylethyl, imidazolyl-(CH₂)—

, or indolyl-(CH₂)—

group, each of which is optionally substituted with 1 or 2 substituents that are each independently F, Cl, Br, I, hydroxy, oxo, cyano, amino, methylamino, dimethylamino, azido, nitro, (C_1-4)alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, carboxamido, SH, S(O)_0-2CH₃, or guanidino.

7. The compound of claim 1 wherein R⁴ is H.

8. The compound of claim 1 wherein one, two, or three of R², R³, R⁵, and R⁶ are H.

9. The compound of claim 1 wherein R⁵ is H, R⁶ is H, or both R⁵ and R⁶ are H.

10. The compound of claim 1 wherein R² and R³ are independently selected from H, F, Cl, OH, or a substituted or unsubstituted C-_1-6 alkyl, phenyl, or benzyl group.

11. The compound of claim 1 wherein R⁵ and R⁶ are independently selected from H, F, Cl, or a substituted or unsubstituted C_1-6 alkyl, phenyl, or benzyl group.

12. The compound of claim 1 wherein each of R², R³, R⁵, and R⁶ is H.

13. The compound of claim 1 wherein the compound is 90 wt. % or greater of a single diastereomer.

14. The compound of claim 1 wherein the compound is 90 wt. % or greater of a single enantiomer.

15. A compound of claim 1 that has Formula II:

16. The compound of claim 15 wherein R⁴ is H.

17. The compound of claim 15 wherein X is O or S.

18. The compound of claim 15 wherein R¹ and R⁴ are independently:

a) H;

b) (C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12)cycloalkyl, (C_3-12)(cycloalkyl)alkyl, (C_3-12)cycloalkenyl, or (C_3-12)(cycloalkenyl)alkyl;

wherein each group is optionally mono- or independently plurisubstituted with R⁷, and wherein the alkyl, alkenyl, and alkynyl groups optionally and independently comprise 1, 2, or 3 groups selected from O, NH, S, SO, SO₂, or a 3, 4, 5, or 6 member divalent carbocyclyl or heterocyclyl group;

wherein

R⁷ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_3-10)cycloalkyl;

—

SR⁸;

—

SOR⁸;

—

SO₂R⁸;

—

COR⁸;

—

CO₂R⁸;

—

CONHR⁸;

—

CON(R⁸)₂;

—

OC(O)NHR⁸;

—

OC(O)N(R⁸)₂, —

OR⁸;

carboxy;

cyano;

nitro;

oxo;

hydroxyl;

hydroxy(C_1-6)alkyl;

hydroxymethyl;

N-hydroxyimino;

trifluoromethyl;

trifluoromethoxy;

sulfamoyl;

sulfonamido;

carbamoyl;

azido;

amidino;

guanidino;

amino, wherein the amino group is optionally mono- or independently plurisubstituted with R⁸, —

SOR⁸, —

SO₂R⁸, —

COR⁸, —

CO₂R⁸, —

CONHR⁸, —

CON(R⁸)₂, —

OR⁸, or —

SR⁸;

aryl;

heterocyclyl;

or heteroaryl;

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

+P2

each R⁸ is independently (C_1-10)alkyl;

(C_2-10)alkenyl;

(C_2-10)alkynyl;

(C_3-10)cycloalkyl;

(C_5-10)cycloalkenyl;

benzyl;

phenethyl;

aryl;

heterocyclyl, or heteroaryl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups are optionally mono- or independently disubstituted with R¹⁰; and

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R¹¹;

R⁹ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_3-10)cycloalkyl;

—

SR⁸;

—

SOR⁸;

—

SO₂R⁸;

—

COR⁸;

—

CO₂R⁸;

—

CONHR⁸;

—

CON(R⁸)₂;

—

OC(O)NHR⁸;

—

OC(O)N(R⁸)₂, —

OR⁸;

carboxy;

cyano;

nitro;

oxo;

hydroxyl;

hydroxy(C_1-6)alkyl;

hydroxymethyl;

N-hydroxyimino;

trifluoromethyl;

trifluoromethoxy;

trifluoromethylthio, sulfamoyl;

sulfonamido;

carbamoyl;

amidino;

guanidino;

phenyl, phenoxy, benzyl;

benzyloxy;

azido;

amino, wherein the amino group is optionally mono- or independently plurisubstituted with R⁸, —

SOR⁸, —

SO₂R⁸, —

COR⁸, —

CO₂R⁸, —

CONHR⁸, —

CON(R⁸)₂, —

OR⁸, or —

SR⁸;

C_1-10)alkylamino;

or (C_1-10)dialkylamino;

R¹⁰ is aryl, heterocyclyl, or heteroaryl, wherein each group is optionally mono- or independently plurisubstituted with R¹¹;

R¹¹ is halogen;

(C_1-10)alkyl;

(C_1-10)alkoxy;

(C_1-10)alkylamino;

(C_1-10)dialkylamino;

phenyl, phenoxy, benzyl;

benzyloxy;

hydroxyl(C_1-6)alkyl;

hydroxymethyl;

nitro;

trifluoromethyl;

trifluoromethoxy;

trifluoromethylthio;

N-hydroxyimino;

cyano;

carboxy;

acetamido;

hydroxy;

sulfonamido;

or amino;

c) phenyl, phenyl fused to a (C_3-10)cycloalkyl;

monocyclic heteroaryl, or monocyclic heteroaryl fused to a (C_3-10)cycloalkyl;

wherein the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

d) indanyl;

1,2,3,4-tetrahydronaphthyl;

—

(CH₂)_j-adamantyl in which j is 0, 1, 2, or 3;

(4-pentylbicyclo[2.2.2]oct-1-yl)amine;

or a [2.2.1] or [3.1.1] bicyclic carbocyclyl group, wherein the indanyl, 1,2,3,4-tetrahydronaphthyl, —

(CH₂)_j-adamantyl, and [2.2.1] or [3.1.1] bicyclic carbocyclyl groups are optionally mono- or independently plurisubstituted with hydroxy, (C_1-8)alkyl, (C_{1- 8})alkoxy, (C_1-8)alkanoyloxy, or R¹²R¹³N—

CO—

O—

, wherein R¹² and R¹³ are independently (C_1-8)alkyl, or phenyl, wherein the alkyl and phenyl groups are optionally mono- or independently plurisubstituted with (C_1-8)alkyl, (C_1-8)alkoxy, halogen, or trifluoromethyl, or R¹² and R¹³ together are (C_3-6)alkylene;

e) R¹⁴(CH₂)_p—

wherein R¹⁴ is pyrrolyl, pyrrolidinyl, 2-oxopyrrolidinyl, imidazolyl, pyrazolyl, thiophenyl, thiazolyl, furanyl, tetrahydrofuranyl, oxazolyl, oxazolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, purinyl, pyrimidinyl, quinolinyl, (C_1-6)alkoxy, phenyl, phenoxy, (C_1-8)cycloalkyl, naphthyl, cyclohexenyl, or adamantyl;

each of which groups is optionally mono- or independently di- or trisubstituted with R¹⁵;

or R¹⁴ is a [3.3.3] bicyclic carbocyclyl group, optionally mono-or independently plurisubstituted with (C_1-8)alkyl; and

p is 0, 1, 2, or 3; and

wherein

R¹⁵ is halogen;

cyano;

nitro;

(C_1-6)alkyl;

(C_1-6)alkoxy;

cycloalkyl;

carboxy;

C(O)NHR⁸;

hydroxy;

hydroxy(C_1-6)alkyl;

hydroxymethyl;

trifluoromethyl;

trifluoromethoxy;

sulfamoyl;

carbamoyl;

sulfonamido;

aryl;

heterocyclyl;

or heteroaryl;

wherein the aryl, heterocyclyl, and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

or

f) (R¹⁶)₂CH(CH₂)_q—

, wherein R¹⁶ is phenyl;

in which the phenyl groups are independently optionally mono- or independently disubstituted with R¹⁵; and

q is 0, 1, 2, or 3.

19. The compound of claim 18 wherein R¹ and R⁴ are independently

a) H;

b) (C_1-12)alkyl, (C_2-12)alkenyl, (C_2-12)alkynyl, (C_3-12)cycloalkyl, or (C_3-12)cycloalkenyl;

wherein each group is optionally mono- or independently plurisubstituted with R⁷;

c) phenyl, phenyl fused to a (C_3-10)cycloalkyl, monocyclic heteroaryl, or monocyclic heteroaryl fused to a (C_3-10)cycloalkyl;

wherein the phenyl and heteroaryl groups are optionally mono- or independently plurisubstituted with R⁹;

d) R¹⁴(CH₂)_p—

;

or

e) (R¹⁶)₂CH(CH₂)_q—

.

20. The compound of claim 15 wherein R¹ is H or a methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclopentyl, cyclopentyl-(CH₂)—

, cyclohexyl, cyclohexyl-(CH₂)—

, phenyl, benzyl, phenylethyl, imidazolyl-(CH₂)—

, or indolyl-(CH₂)—

group, each of which is optionally substituted with 1 or 2 substituents that are each independently F, Cl, Br, I, hydroxy, oxo, cyano, amino, methylamino, dimethylamino, azido, nitro, (C_1-4)alkoxy, trifluoromethyl, trifluoromethoxy, carboxyl, carboxamido, SH, S(O)_0-2CH₃, or guanidino.

21. The compound of claim 15 wherein the compound is 90 wt. % or greater of a single diastereomer.

22. The compound of claim 15 wherein the compound is 90 wt. % or greater of a single enantiomer.

39. A method for inhibiting dipeptidyl peptidase-IV comprising contacting dipeptidyl peptidase-IV with a compound of claim 1.

40. The method of claim 39 wherein dipeptidyl peptidase-IV is inhibited by greater than 5-fold relative to one or more other dipeptidyl peptidases.

41. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII.

42. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII.

43. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-IX.

44. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over fibroblast activation protein.

45. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VIII and fibroblast activation protein.

46. The method of claim 39 wherein the compound of Formula I selectively inhibits dipeptidyl peptidase-IV over dipeptidyl peptidase-VII, dipeptidyl peptidase-VIII, and fibroblast activation protein.

47. A method for treating controlling or preventing conditions mediated by dipeptidyl peptidase-IV inhibition, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1.

48. The method of claim 47 wherein the compound inhibits dipeptidyl peptidase-IV by 5-fold or more versus at least one other dipeptidyl peptidase enzyme.

49. The method of claim 47 wherein insulin resistance is a component of the condition.

50. The method of claim 47 whereby islet neogenesis, β

-cell survival, or insulin biosynthesis is enhanced.

51. The method of claim 47 wherein the condition is one or more of (1) hyperglycemia, (2) low glucose tolerance, (3) insulin resistance, (4) obesity, (5) lipid disorders, (6) atherosclerosis and its sequelae, (7) vascular restenosis, (8) irritable bowel syndrome, (9) inflammatory conditions, (10) growth hormone deficiency, (11) HIV infection, (12) pancreatitis, (13) abdominal obesity, (14) neurodegenerative disease, (15) multiple sclerosis, (16) retinopathy, (17) nephropathy, (18) neuropathy, (19) Syndrome X, (20) ovarian hyperandrogenism, (21) allograft rejection in transplantation, (22) diabetes, (23) neutropenia, (24) anemia, (25) neuronal disorders, (26) tumor growth and metastasis, (27) benign prostatic hypertrophy, (28) gingivitis, (29) hypertension, (30) osteoporosis, (31) dysmetabolic syndrome, (32) diabetic complications, (33) impaired glucose homeostasis, (34) infertility, (35) polycystic ovary syndrome, (36) growth disorders, (37) frailty, (38) autoimmune diseases, (39) intestinal diseases, or (40) anorexia nervosa.

52. The method of claim 51 wherein the condition is diabetes.

53. The method of claim 52 wherein the diabetes is non-insulin dependent diabetes mellitus.

54. The method of claim 52 wherein the diabetes is insulin dependent diabetes mellitus.

55. The method of claim 51 wherein the condition is hyperglycemia.

56. The method of claim 51 wherein the condition is obesity.

57. The method of claim 51 wherein the condition is insulin resistance.

58. The method of claim 51 wherein the lipid disorders are selected from dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, low HDL, or high LDL.

59. The method of claim 51 wherein the inflammatory condition is inflammatory bowel disease, Crohn'"'"'s disease, ulcerative colitis, or rheumatoid arthritis.

60. The method of claim 51 further comprising administering one or more other suitable compounds selected from the group consisting of:

a) Other dipeptidyl peptidase-IV inhibitors;

b) Insulin sensitizers selected from the group consisting of (i) PPAR agonists, (ii) biguanides, and (iii) protein phosphatase-1B inhibitors;

c) Insulin or insulin mimetics;

d) Sulfonylureas or other insulin secretagogues;

e) α

-glucosidase inhibitors;

f) glucagons receptor agonists;

g) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

h) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;

i) GIP, GIP mimetics, and GIP receptor agonists;

j) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

k) Cholesterol lowering agents selected from the group consisting of HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PPARα

agonists, PPARα

/γ

dual agonists, inhibitors of cholesterol absorption, acyl CoA;

cholesterol acyltransferase inhibitors, and anti-oxidants;

l) PPARδ

agonists;

m) Anti-obesity compounds;

n) An ileal bile acid transporter inhibitor;

o) Anti-inflammatory agents;

p) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and

q) EPO, EPO mimetics, and EPO receptor agonists.

61. The method of claim 51 wherein the condition is diabetes and the method further comprises administering to a mammal in need of such treatment a therapeutically effective amount of other dipeptidyl peptidase-IV inhibitors;

insulin sensitizers;

insulin or insulin mimetics;

sulfonylureas or other insulin secretagogues;

α

-glucosidase inhibitors;

glucagons receptor agonists;

GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;

GIP, GIP mimetics, and GIP receptor agonists;

PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

PPARδ

agonists;

anti-obesity compounds;

or an ileal bile acid transporter inhibitor.

62. The method of claim 51 wherein the one or more conditions are selected from the group consisting of hypercholesterolemia, atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, hypertriglyceridemia, and dyslipidemia, and further comprising administering to a mammal in need of such treatment a therapeutically effective amount of an HMG-CoA reductase inhibitor.

63. The method of claim 62 wherein the HMC-CoA reductase inhibitor is a statin.

64. The method of claim 63 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.

65. The method of claim 62 wherein the condition is atherosclerosis.

66. The method of claim 65 wherein the HMC-CoA reductase inhibitor is a statin.

67. The method of claim 66 wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, itavastatin, ZD-4522 and rivastatin.

68. The method of claim 51 for the treatment, control, or prevention of obesity, further comprising administering to a mammal in need of such treatment a therapeutically effective amount of an anti-obesity agent.

69. The method of claim 68 wherein the anti-obesity agent is a beta-3 adrenergic agonist, a lipase inhibitor, a serotonin and dopamine reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, a fatty acid oxidation upregulator, or a mixture of any two or more thereof.

70. The method of claim 68 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, mazindol, or a mixture of any two or more thereof.

71. The method of claim 51 wherein the condition is neutropenia, and further comprising administering to a mammal in need of such treatment a therapeutically effective amount of a neutrophilic agent.

72. The method of claim 71 wherein the neutrophilic agent is G-CSF, a G-CSF mimetic, a G-CSF receptor agonist or a mixture of any two or more thereof.

73. The method of claim 71 wherein the neutrophilic agent is pegfilgrastim, filgrastim, lenograstim, nartograstim, or a mixture of any two or more thereof.

74. The method of claim 51 wherein the condition is anemia, and further comprising administering to a mammal in need of such treatment a therapeutically effective amount of a erythropoietin agonist.

75. The method of claim 74 wherein the erythropoietin agonist is EPO, an EPO mimetic, an EPO receptor agonist, or a mixture of any two or more thereof.

76. The method of claim 74 wherein the erythropoietin agonist is epoetin alfa, darbepoetin alfa, or a mixture of any two or more thereof.

77. A pharmaceutical composition comprising a compound of claim 1 together with at least one pharmaceutically acceptable carrier or diluent.

78. A pharmaceutical combination, comprising:

a) a compound of claim 1;

b) one or more compounds selected from the group consisting of;

i) Other dipeptidyl peptidase-IV inhibitors;

ii) Insulin sensitizers selected from the group consisting of PPAR agonists, biguanides, and protein phosphatase-1B inhibitors;

iii) Insulin or insulin mimetics;

iv) Sulfonylureas or other insulin secretagogues;

v) α

-glucosidase inhibitors;

vi) glucagons receptor agonists;

vii) GLP-1, GLP-1 mimetics, and GLP-1 receptor agonists;

viii) GIP, GIP mimetics, and GIP receptor agonists;

ix) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

x) GLP-2, GLP-2 mimetics, and GLP-2 receptor agonists;

xi) Cholesterol lowering agents selected from the group consisting of HMG-CoA reductase inhibitors, sequestrants, nicotinyl alcohol, nicotinic acid or a salt thereof, PPARα

agonists, PPARα

/γ

dual agonists, inhibitors of cholesterol absorption, acyl CoA;

cholesterol acyltransferase inhibitors, and anti-oxidants;

xii) PPARδ

agonists;

xiii) Anti-obesity compounds;

xiv) An ileal bile acid transporter inhibitor;

xv) Anti-inflammatory agents;

xvi) G-CSF, G-CSF mimetics, and G-CSF receptor agonists; and

xvii) EPO, EPO mimetics, and EPO receptor agonists.

79. The pharmaceutical combination of claim 78 further comprising c) a pharmaceutically acceptable carrier.

80. The pharmaceutical combination of claim 78 wherein the one or more compounds is an HMG-CoA reductase inhibitor.

81. The pharmaceutical combination of claim 78 wherein the one or more compounds are an antidiabetic agent.

82. The pharmaceutical combination of claim 81 further comprising an anti-obesity agent, a lipid-modulating agent, or both an anti-obesity agent and a lipid-modulating agent, and wherein the antidiabetic agent is not a dipeptidyl peptidase-IV inhibitor.

83. The pharmaceutical combination of claim 82 wherein the antidiabetic agent is 1, 2, 3 or more compounds selected from the group consisting of a biguanide, a sulfonyl urea, a glucosidase inhibitor, a PPAR γ

agonist, a PPAR α

/γ

dual agonist, an SGLT2 inhibitor, an aP2 inhibitor, a glycogen phosphorylase inhibitor, an AGE inhibitor, an insulin sensitizer, a glucagon-like peptide-1 (GLP-1) or mimetic thereof, insulin and a meglitinide.

84. The pharmaceutical combination of claim 82 wherein the antidiabetic agent is 1, 2, 3 or more compounds selected from the group consisting of metformin, glyburide, glimepiride, glipyride, glipizide, chlorpropamide, gliclazide, acarbose, miglitol, pioglitazone, troglitazone, rosiglitazone, insulin, Gl-262570, isaglitazone, JTT-501, NN-2344, L895645, YM-440, R-119702, AJ9677, repaglinide, nateglinide, KAD1129, APR-HO39242, GW-409544, KRP297, AC2993, Exendin-4, LY307161, NN2211, and LY315902.

85. The pharmaceutical combination according to claim 82 wherein the compound of Formula I is present in a weight ratio to the antidiabetic agent from about 0.01 to about 100:

1.

86. The pharmaceutical combination of claim 82 wherein the anti-obesity agent is a beta 3 adrenergic agonist, a lipase inhibitor, a serotonin (and dopamine) reuptake inhibitor, a thyroid receptor beta compound, an anorectic agent, a fatty acid oxidation upregulator, or a mixture of any two or more thereof.

87. The pharmaceutical combination of claim 86 wherein the anti-obesity agent is orlistat, ATL-962, AJ9677, L750355, CP331648, sibutramine, topiramate, axokine, dexamphetamine, phentermine, phenylpropanolamine, famoxin, mazindol, or a mixture of any two or more thereof.

88. The pharmaceutical combination of claim 82 wherein the lipid-modulating agent is an MTP inhibitor, an HMG CoA reductase inhibitor, a squalene synthetase inhibitor, a fibric acid derivative, an upregulator of LDL receptor activity, a lipoxygenase inhibitor, an ACAT inhibitor, a cholesteryl ester transfer protein inhibitor, an ATP citrate lyase inhibitor, or a mixture of any two or more thereof.

89. The pharmaceutical combination of claim 88 wherein the lipid-modulating agent is pravastatin, lovastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, nisvastatin, visastatin, fenofibrate, gemfibrozil, clofibrate, implitapide, CP-529,414, avasimibe, TS-962, MD-700, LY295427, or a mixture of any two or more thereof.

90. The pharmaceutical combination of claim 82 wherein the compound of Formula I is present in a weight ratio to the lipid-modulating agent from about 0.01 to about 100:

1.

91. A pharmaceutical combination comprising a DPP-IV inhibitor compound according to claim 1 and an agent for treating an agent for treating polycystic ovary syndrome, an agent for treating a growth disorder and/or frailty, an anti-arthritis agent, an agent for preventing or inhibiting allograft rejection in transplantation, an agent for treating autoimmune disease, an anti-AIDS agent, an agent for treating inflammatory bowel disease/syndrome, an agent for treating anorexia nervosa, an anti-osteoporosis agent, an anti-obesity agent or a mixture of any two or more thereof.

23. A compound that is an 8-member bicyclic heterocycle comprising a pyrrolidinonyl ring, wherein the heterocycle is substituted with a cyano group and a basic group having a pKa of from about 6 to about 10, and wherein the heterocycle inhibits DPP-IV with a Ki of 10 uM or less.

24. The compound of claim 23 wherein the basic group is an aminoalkyl or amino group.

25. The compound of claim 23 having the Formula III:

26. The compound of claim 25 wherein each of R², R³, R⁵, and R⁶ is H.

27. The compound of claim 25 wherein the compound is

6-Amino-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-methyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile,

6-Amino-6-ethyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-isopropyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclopentyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclohexyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-isobutyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-sec-butyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-5-oxo-6-phenethyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-benzyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-cyclohexylmethyl-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride,

6-Amino-6-(4-fluoro-phenyl)-5-oxo-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride, or

6-Amino-5-oxo-6-phenyl-hexahydro-pyrrolo[2,1-b]thiazole-3-carbonitrile hydrochloride.

28. A compound that has the Formula IV:

29. The compound of claim 28 wherein R⁴ is H and R^4a is an amino protecting group.

30. The compound of claim 28 having the Formula IVA:

31. The compound of claim 30 that has the Formula IVB.

32. The compound of claim 31 wherein R¹⁷ is an unsubstituted t-butyl, benzyl, or fluoren-9-ylmethyl group.

33. The compound of claim 30 wherein X is S.

34. A method of making a compound of claim 28 comprising exposing a compound of Formula V, stereoisomers, solvates, hydrates, tautomers, prodrugs, pharmaceutically acceptable salts, or mixtures thereof,

35. The method of claim 34 wherein the dehydrating agent is trifluoroacetic anhydride or methyl N-(triethylammoniosulfonyl)carbamate.

36. The method of claim 34 further comprising removing the amino protecting group or groups of the compound of Formula IV to provide a compound of Formula III:

37. The method of claim 34 wherein the compound of Formula V has the structure of Formula VA:

38. The method of claim 37 further comprising removing the amino protecting group or groups of the compound of Formula VA to provide a compound of Formula I: